NM_022552.5(DNMT3A):c.1792C>T (p.Arg598Ter) AND Tatton-Brown-Rahman overgrowth syndrome

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Dec 1, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001382894.5

Allele description [Variation Report for NM_022552.5(DNMT3A):c.1792C>T (p.Arg598Ter)]

NM_022552.5(DNMT3A):c.1792C>T (p.Arg598Ter)

Gene:

DNMT3A:DNA methyltransferase 3 alpha [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

2p23.3

Genomic location:

Preferred name:

NM_022552.5(DNMT3A):c.1792C>T (p.Arg598Ter)

HGVS:

NC_000002.12:g.25244214G>A
NG_029465.2:g.103377C>T
NM_001320893.1:c.1336C>T
NM_001375819.1:c.1123C>T
NM_022552.5:c.1792C>TMANE SELECT
NM_153759.3:c.1225C>T
NM_175629.2:c.1792C>T
NP_001307822.1:p.Arg446Ter
NP_001362748.1:p.Arg375Ter
NP_072046.2:p.Arg598Ter
NP_715640.2:p.Arg409Ter
NP_783328.1:p.Arg598Ter
LRG_459t2:c.1225C>T
LRG_459t4:c.1792C>T
LRG_459:g.103377C>T
LRG_459p2:p.Arg409Ter
LRG_459p4:p.Arg598Ter
NC_000002.11:g.25467083G>A
NM_175629.2:c.1792C>T
NR_135490.2:n.2023C>T

Protein change:

R375*

Links:

dbSNP: rs568207978

NCBI 1000 Genomes Browser:

rs568207978

Molecular consequence:

NR_135490.2:n.2023C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NM_001320893.1:c.1336C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001375819.1:c.1123C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_022552.5:c.1792C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_153759.3:c.1225C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_175629.2:c.1792C>T - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:: Tatton-Brown-Rahman overgrowth syndrome
Synonyms:: Tatton-Brown-rahman syndrome; Tall stature-intellectual disability-facial dysmorphism syndrome
Identifiers:: MONDO: MONDO:0014382; MedGen: C4014545; Orphanet: 404443; OMIM: 615879

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acetylcholine receptor subunit alpha-like [Amphiprion ocellaris]
acetylcholine receptor subunit alpha-like [Amphiprion ocellaris]
gi|1308428967|ref|XP_023135032.1|

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001581851	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 1, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 24614070, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001581851

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 1, 2023)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Mutations in the DNA methyltransferase gene DNMT3A cause an overgrowth syndrome with intellectual disability.

Tatton-Brown K, Seal S, Ruark E, Harmer J, Ramsay E, Del Vecchio Duarte S, Zachariou A, Hanks S, O'Brien E, Aksglaede L, Baralle D, Dabir T, Gener B, Goudie D, Homfray T, Kumar A, Pilz DT, Selicorni A, Temple IK, Van Maldergem L, Yachelevich N; Childhood Overgrowth Consortium., et al.

Nat Genet. 2014 Apr;46(4):385-8. doi: 10.1038/ng.2917. Epub 2014 Mar 9. Erratum in: Nat Genet. 2014 Jun;46(6):657.

PubMed [citation]

PMID:: 24614070
PMCID:: PMC3981653

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001581851.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This sequence change creates a premature translational stop signal (p.Arg598*) in the DNMT3A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DNMT3A are known to be pathogenic (PMID: 24614070). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with DNMT3A-related conditions. ClinVar contains an entry for this variant (Variation ID: 1070654). For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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